This Project represents the merger of three Projects from the previous Center and was viewed as highly integrated and of high significance for the overall goals of the Center. We thank the committee for these praises and are hopeful that the revised application maintains the strengths noted in the original proposal. The committee felt the "top-down" approach in which we evaluate compounds that are currentiy under investigation by our clinical partners at the University of Pennsylvania and the University of Virginia was highly innovative. In this revised Project 1, we propose to examine the effects of both modafinil and topiramate, as well as other drugs evaluated clinically, drugs currently in the pipeline for clinical evaluation and mechanistically related drugs in our animal models. The strategies for testing are now described in detail in this Project. There were two general weaknesses noted by the committee that reduced the overall level of enthusiasm. One concern was related to the experimental design for the monkey studies and the second concern involved the potential development of treatment drugs from the "bottom-up" strategy. In this revision, we have cleariy described how many monkeys will be tested with each drug, provided power calculations justifying the number of monkeys to observe effects for behavior and imaging {Project 2), cleariy identify which monkeys will be studied in cognitive tasks, and what criteria would be necessary for naive monkeys to be purchased and used in Projects 2 and 3. Furthermore, we now provide detailed hypotheses for each experiment, as well as alternative possibilities. To address the second general concern - will we be able to take any promising findings into the clinic - we have revised the focus from "bottom-up" to "mechanistic" and will concentrate on understanding the neuropharmacological mechanisms associated with a positive treatment outcome. As described in more detail in the Center Overview, we did not mean to imply that we are attempting to develop new drugs, but rather, to understand the basic science mediating treatment efficacy. We have rewritten the Experimental Design to clearly show that these are hypothesis-driven studies, which will provide valuable information to clinicians. The revised application has incorporated all ofthe suggestions ofthe committee, as outiined below. Because each section was rewritten, there are no demarcations in the revised proposal indicating specific changes. The revision contains all ofthe Ingredients that were deemed unique by the committee and in response to the critiques, we have reduced the Background section and expanded the section on Experimental Design to include hypotheses and expected outcomes.